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Begin with BRAF. Searching for a target in metastatic melanoma?. Overview. Oncogenic BRAF can result from mutations in the BRAF gene, which may cause the protein to become overactive 1 One common BRAF mutation (BRAF V600 ) is implicated in diverse malignancies 2,3 - PowerPoint PPT Presentation
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Begin with BRAFSearching for a target in metastatic melanoma?
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Overview
Oncogenic BRAF can result from mutations in the BRAF gene, which may cause the protein to become overactive1
One common BRAF mutation (BRAFV600) is implicatedin diverse malignancies2,3
Genentech is currently researching oncogenic BRAF as a novel therapeutic target
21. Sharma et al. Cancer Res. 2005;65:2412-2421. 2. Wong. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 3. Wellbrock et al. Biochem Pharmacol. 2010;80:561-567.
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Table of contents
The role of RAS-RAF proteins in the RAS-RAF pathway
The BRAF protein kinase
Oncogenic BRAF
Targeting oncogenic BRAF
3
BRF0000320900
The role of RAS-RAF proteins in the RAS-RAF pathway
41. Wong. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wan et al. Cell. 2004;116:855-867. 3. McCubrey et al. Adv Enzyme Regul. 2006;46:249-279.
RAS
BRAF
ERK
MEK
RAF proteins play a role in the regulation of essential biologic functions1-3
Cell growth Cell proliferation Cell differentiation
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RAS-RAF signaling in normal cells
1. McCubrey et al. Adv Enzyme Regul. 2006;46:249-279.
Activation of the RAS-RAF signaling cascade occurs via the following sequential steps1: Activation by growth factors Activation of RAS Activation of RAF Phosphorylation of MEK Phosphorylation of ERK Activation of transcription factors
Result1
Cell proliferation Cell survival
BRF0000320900
Table of contents
The role of RAS-RAF proteins in the RAS-RAF pathway
The BRAF protein kinase
Oncogenic BRAF
Targeting oncogenic BRAF
6
BRF0000320900
The BRAF protein kinase
71. Wan et al. Cell. 2004;116:855-867.
BRAF is a protein kinase encoded by the BRAF gene and plays an important role as an intermediary in the RAS-RAF signaling cascade1
BRF0000320900
Table of contents
The role of RAS-RAF proteins in the RAS-RAF pathway
The BRAF protein kinase
Oncogenic BRAF
Targeting oncogenic BRAF
8
BRF0000320900
Oncogenic BRAF
1. McCubrey et al. Adv Enzyme Regul. 2006;46:249-279. 2. Pritchard et al. Biochem Soc Trans. 2007;35:1329-1333. 3. Cho et al. Int J Cancer. 2006;119:1858-1862.
V600E mutation
BRAF mutations at position 600 (BRAFV600) can lead to overactive BRAF signaling1
The most common BRAF mutation, BRAFV600E, is implicated in:
~50% of melanoma tumors1
~40% of papillary thyroid tumors1,2
~30% of serous ovarian tumors2
~10% of colorectal tumors3
~10% of prostate tumors3
9
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Oncogenic BRAF signaling
1. Wong. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. McCubrey et al. Adv Enzyme Regul. 2006;46:249-279.
Excessive cell proliferation
Resistance to apoptosis
An overactive signaling cascade1
Independent of growth factors Uncontrolled signaling
Result1,2
BRF0000320900
Table of contents
The role of RAS-RAF proteins in the RAS-RAF pathway
The BRAF protein kinase
Oncogenic BRAF
Targeting oncogenic BRAF
11
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Research into oncogenic BRAF
Research is currently ongoing to detect and target oncogenic BRAF
Inhibition of oncogenic BRAF is an opportunity for precise molecular targeting1
Research efforts are also underway to use molecular biology techniques to detect the BRAFV600 mutation2
1. Wellbrock et al. Biochem Pharmacol. 2010;80:561-567. 2. Lin et al. Br J Cancer. 2011;104:464-468.
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Overview of metastatic melanoma disease state
1. Bhatia et al. Oncology. 2009;23:488-496. 2. Korn et al. J Clin Oncol. 2008;26:527-534. 3. McCubrey et al. Adv Enzyme Regul. 2006;46:249-279. 4. Skarin, ed. Atlas of Diagnostic Oncology. 4th ed. Philadelphia, PA: Mosby, Inc; 2010:467.
Metastatic melanoma is an important area for continued research and development of strategies for patient management
Median overall survival of ~8 months1
1-year survival rate of ~25%2
~50% of metastatic melanoma tumors have the BRAFV600 mutation3
Reprinted with permission from Elsevier.4
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References
Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology. 2009;23:488-496.
Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.
Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of Phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future Phase II trials. J Clin Oncol. 2008;26:527-534.
Lin J, Goto Y, Murata H, et al. Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression. Br J Cancer. 2011;104:464-468.
McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279.
Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333.
Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. Mutant V599EB-raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65:2412-2421.
Skarin AT, ed. Atlas of Diagnostic Oncology. 4th ed. Philadelphia, PA: Mosby, Inc; 2010:467.
Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867.
Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567.
Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35.
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